Many biological actions, for instance, response to certain stimuli and natural biological processes, are controlled by factors, such as cytokines. Many cytokines act through receptors by engaging the receptor and producing an intracellular response.
For example, tumor necrosis factors (TNF) alpha and beta are cytokines which act through TNF receptors to regulate numerous biological processes, including in host defense processes such as protection against infections, and pathological conditions such as shock responses and inflammatory disease condistions. TNF-X belongs to the "TNF-ligand" superfamily of which 19 members have been identified so far. These ligands mediate their effects through interactions with cell surface or secreted, decoy, receptors, expressed by many different cell types, and which themselves now form a superfamily with 24 indentified members to date.
Among the ligands there are included TNF-.alpha., lymphotoxin.alpha. (LT-.alpha., also known as TNF-.beta.), LT-.beta. (found in heterotrimeric complexes, LT-.alpha.2-.beta.), FasL, CD40L, CD27L, CD30L, 4-1BBL, OX40L and nerve growth factor (NGF)). The receptor superfamily includes the p55 and p75 TNF receptor, FAS APO-1, CD40, CD27, CD30, 4-1BB, OX40 and the low affinity p75 NGF-receptor (Meager, A., Biologicals, 22:291-295 (1994)).
Many members of the TNF-ligand superfamily are expressed by cells of the immune and hematopoietic system which underscores their role in differentian of the cells of the immune cells and functional responses in host defense mechanisms (Meager, A., supra).
Considerable insight into the essential functions of several members of the TNF receptor family has been gained from the identification and creation of mutants that abolish the expression of these proteins. For example, naturally occurring mutations in the FAS antigen and its ligand cause lymphoproliferative disease (Watanabe-Fukunaga, R., et al., Nature 356:314 (1992)), perhaps reflecting a failure of programmed cell death. Mutations of the CD40 ligand cause an X-linked immunodeficiency state characterized by high levels of immunoglubulin M and low levels of immunoglobulin G in plasma, indicating faulty T-cell-dependent B-cell activation (Allen, R. C. et al., Science 259:990 (1993)). Targeted mutations of the low affinity nerve growth factor receptor cause a disorder characterized by faulty sensory innovation of peripheral structures (Lee, K. F. et al, Cell 69:737 (1992)).
TNF-.alpha. and LT-.alpha. are capable of binding to two TNF receptors (the 55- and 75-kd TNF receptors). A large number of biological effects are elicited by TNF-.alpha. and LT-.alpha., acting through their receptors, include hemorrhagic necrosis of transplanted tumors, cytotoxicity, a role in endotoxic shock, inflammation, immunoregulation, proliferation and anti-viral responses, as well as protection against the deleterious effects of ionizing radiation. TNF-.alpha. and LT-.alpha. are involved in the pathogenesis of a wide range of diseases, including endotoxic shock, cerebral malaria, tumors, autoimmuine diseases, allergic disorders, AIDS and graft rejection (Beutler, B. and Von Huffel, C., Science 264:667-668 (1994)). Mutations in the p55 Receptor cause increased susceptibility to microbial infection.
Moreover, an about 80 amino acid domain near the C-terminus of TNFR1 (p55) and Fas was reported as the "death domain," which is responsible for transducing signals for programmed cell death (Tartaglia et al., Cell 74:845 (1993)).
The effects of TNF ligand and TNF receptor families are varied and influence numerous functions, both normal and abnormal, in the biological processes of mammalian and non-mammalian species. There is a clear need, therefore, for identification and characterization of such receptors and ligands that influence biological activity, both normally and in disease states. In particular, there is a need to isolate and characterize novel members of the TNF receptor family.
This indicates that these receptors have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further receptors which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, chronic and acute inflammation, arthritis (including rheumatoid arthritis), septicemia, autoimmune diseases (e.g. inflammatory bowel disease, psoriasis), transplant rejection, graft vs. host disease, infection, stroke, ischernia, acute respiratory disease syndrome, asthma, restenosis, brain injury, AIDS, Bone diseases, cancer atheroschlerosis, and Alzheimers disease.